Flecainide-containing liquid pharmaceutical composition and process for its preparation

Abstract

The present invention relates to a liquid pharmaceutical composition for administration to the pediatric population and to adults who are unable to swallow solid dosage forms, comprising a therapeutically effective amount of flecainide or a pharmaceutically acceptable salt thereof as an active ingredient, and to a process for the preparation of said liquid pharmaceutical composition.

Description

[Technical Field]

[0001] The present invention relates to a pharmaceutical composition for oral administration, in particular to a liquid pharmaceutical composition comprising a therapeutically effective amount of flecainide or a pharmaceutically acceptable salt thereof as an active ingredient for administration to the pediatric population and adults who are unable to swallow solid dosage forms. Furthermore, the present invention relates to a process for the preparation of the above-mentioned liquid pharmaceutical composition. [Background technology]

[0002] Flecainide is an antiarrhythmic drug used to treat tachyarrhythmias, including atrial fibrillation, supraventricular tachycardia, or ventricular tachycardia, especially when conventional treatments are ineffective.

[0003] Flecainide is commercially available as a solid formulation (tablets) and as an intravenous solution. When no commercially available oral liquid is available, pharmacies generally prepare a suspension from the available solid formulation by adding purified water. If necessary, syrup can be added to make it easier to swallow. A similar process has been used with flecainide, where commercially available tablets are crushed and mixed with water and syrup or a sweetener to prepare an oral suspension that is easier for patients to swallow.

[0004] Therefore, when necessary, solid dosage forms must be formulated into suspensions for infants and children. Unfortunately, errors in the preparation and administration of such suspensions prepared from solid dosage forms have occasionally led to cardiac emergencies and serious overdoses requiring immediate therapeutic intervention. Furthermore, the resulting suspensions have very limited stability and cannot be stored for long periods of time.

[0005] Additionally, there is a patient population that has difficulty swallowing solid dosage forms such as tablets and capsules. The majority of children under the age of 7-8 years prefer to take oral liquids over solid dosage forms. Elderly patients, or those suffering from certain illnesses, often have difficulty swallowing commonly prescribed oral solid dosage forms and therefore prefer oral liquids for administering their medications.

[0006] US Patent No. US3900481 discloses flecainide and its salts, along with methods for preparing them. Flecainide acetate is known chemically as N-(2-piperidinylmethyl)-2,5-bis(2,2,2-trifluoroethoxy)benzamide monoacetate.

[0007] Flecainide acetate is a white to slightly yellowish white crystalline powder that dissolves in water and absolute alcohol, with a water solubility of approximately 48.0 mg / mL.

[0008] Flecainide acetate is highly soluble and permeable, making it a Class I drug under the Biopharmaceutical Classification System (BCS). However, because the suspension is prepared by crushing tablets, the final formulation remains in the form of a suspension rather than a solution due to the excipients contained in the tablets (which may or may not be soluble in water).

[0009] Therefore, there remains a need for a liquid pharmaceutical formulation of flecainide acetate that exhibits adequate release of flecainide acetate and a process for obtaining the same in good yield, which overcomes the problems associated with the prior art and provides a process that is suitable for oral administration without any stability or dosage uniformity problems. Summary of the Invention

[0010] Therefore, an object of the present invention is to provide a storage-stable liquid pharmaceutical composition for oral administration comprising flecainide or a pharmaceutically acceptable salt thereof as an active ingredient, which overcomes the drawbacks of the prior art.

[0011] Another object of the present invention is to provide a storage-stable liquid preparation containing flecainide or a pharmaceutically acceptable salt thereof as an active ingredient, which is safe and effective, has a sufficient shelf life, and has good pharmacological properties.

[0012] It is a further object of the present invention to provide a suitable process for the effective and reproducible preparation of a shelf-stable liquid pharmaceutical composition for oral administration containing flecainide or a pharmaceutically acceptable salt thereof as an active ingredient.

[0013] In accordance with the above-mentioned object of the present invention, there is provided a storage-stable liquid composition for oral administration, which comprises a therapeutically effective amount of flecainide or a pharmaceutically acceptable salt thereof as an active ingredient, said active ingredient being present in an amount of about 0.1 to about 3.0% w / v, wherein weight / volume percentage is expressed in g / 100 mL, and said composition having a pH value of less than 4.0.

[0014] According to another embodiment of the present invention, there is provided a shelf-stable liquid composition for oral administration comprising 0.5% flecainide acetate, a citrate buffer system comprising sucralose, citric acid, acetic acid or a mixture thereof, and 0.6 to 1.2 mg / mL sodium benzoate, wherein said composition has a pH value in the range of 2.8 to 3.2.

[0015] According to another embodiment of the present invention, there is provided a process for the preparation of a shelf-stable liquid composition for oral administration comprising a therapeutically effective amount of flecainide or a pharmaceutically acceptable salt thereof as an active ingredient, wherein said active ingredient is in an amount of about 0.1 to about 3.0% w / v, wherein weight / volume percentage is expressed in g / 100 mL, said process comprising the steps of: (a) dissolving at least one excipient selected from a buffer and / or a preservative in purified water; (b) adding the entire amount of flecainide or a salt thereof to the solution obtained in step (a) and stirring for an appropriate time until it is completely dissolved; (c) optionally adding to the solution of step (b) at least one excipient selected from a sweetener and / or a flavoring agent; and (d) Adjust the pH of the final solution to less than 4.0 using a suitable hydrochloric acid or sodium hydroxide solution.

[0016] Further preferred embodiments of the present invention are defined in dependent claims 2 to 10 and 13 to 15. Other objects and advantages of the present invention will become apparent to those skilled in the art in view of the following detailed description. DETAILED DESCRIPTION OF THE INVENTION

[0017] For the purposes of the present invention, a liquid pharmaceutical composition for oral administration comprising flecainide or a pharmaceutically acceptable salt thereof as an active ingredient is considered to be "stable" if the precipitation of said active ingredient is less or slower than that which occurs in itself and / or in known pharmaceutical compositions during storage.

[0018] An excipient is considered to be "incompatible" with the active ingredient or its salt if it accelerates the degradation of the active ingredient, i.e., if the active ingredient precipitates to a greater extent or faster in the presence of the excipient than it would precipitate alone. The terms "incompatible," "compatible," and "compatible" are defined accordingly.

[0019] The objective of this invention was to develop a liquid formulation containing flecainide to achieve a potent therapeutic effect and ensure patient compliance and convenience in the treatment of cardiac arrhythmias, including atrial fibrillation, supraventricular tachycardia, and / or ventricular tachycardia. To this end, several different solutions were prepared and their stability or incompatibility was studied. These studies investigated the formation of solid precipitates during product storage to assess the influence of traditionally used excipients, such as cosmetic solvents, buffers, preservatives, sweeteners, and flavoring agents.

[0020] Surprisingly, it has been found that the object of the present invention can be achieved by preventing the formation of precipitates and improving the physicochemical stability of the active ingredient by adjusting the concentration of the active ingredient in the final solution and the pH value of the mixture, and by controlling the order of addition of the active ingredient and excipients. By overcoming this technical obstacle, it has become possible to prepare a storage-stable composition containing an effective amount of flecainide acetate.

[0021] Thus, in a first aspect, the present invention provides a storage-stable liquid composition for oral administration comprising about 0.1% to about 3.0% w / v flecainide acetate, expressed in weight / volume units (g / 100 mL). In the liquid composition of the present invention, flecainide may be used in different solvates or degrees of hydration, preferably as the acetate salt of flecainide.

[0022] In a preferred embodiment, the composition contains about 0.5% w / v flecainide acetate. In addition to flecainide acetate, the composition of the present invention may contain excipients suitable for oral liquid formulations, and preferably a cosolvent, a solubilizer / surfactant, a pH buffer or pH adjuster, a preservative, a sweetener, and a flavoring agent. In a preferred embodiment, the composition contains, independently of each other, citric acid as a buffering agent, sodium benzoate as a preservative, sucralose as a sweetener, cherry flavoring as a flavoring agent, and sodium hydroxide or hydrochloric acid for adjusting the pH value.

[0023] To ensure product stability, the pH value of the composition is preferably adjusted to a range below 4.0. It has been found that outside this pH range, precipitates may form during product storage, regardless of the addition of solubilizers.

[0024] In the initial fundamental research related to the present invention, it was discovered that the process of formulating a liquid formulation containing flecainide acetate resulted in unexpected stability issues when the pH of the composition exceeded 7.0. Precipitation was observed, revealing API incompatibility at pH values ​​above 7.0. The best results, in terms of the absence of precipitate, were observed in the pH range below 4.0, with particularly good results obtained in the pH range of 2.8 to 3.2. It was also noticed that the order of addition of the active ingredient and excipients in steps (a) and (b) appeared to add robustness to the overall stability of the final product.

[0025] The liquid composition of the present invention is used to prepare an oral solution. For this purpose, the liquid solution is filled into a container suitable for oral use and the container is optionally sealed with a screw cap.

[0026] In a further aspect, the present invention relates to the use of the liquid composition for treating a cardiac condition (eg, cardiac arrhythmia) in a subject in need thereof.

[0027] The pharmaceutical compositions of the present invention may also contain one or more additional formulation components selected from a wide variety of excipients. Depending on the desired properties of the composition, any number of components may be selected, alone or in combination, based on their known use in preparing liquid compositions for oral administration.

[0028] Such ingredients include, but are not limited to, co-solvents, buffers, sweeteners, flavoring agents, and preservatives.

[0029] Any excipient must be compatible with flecainide or its salt so as not to interfere with the flecainide or its salt in the composition.

[0030] Furthermore, to overcome problems associated with the unfavourable pharmaceutical technical properties of these substances and to extend the shelf life of the pharmaceutical product and to provide a product exhibiting good stability, bioavailability and palatability, optional excipients may be added to the composition, provided that they are compatible with the active ingredient of the composition.

[0031] The compositions of the present invention may further comprise additives (alone or in combination) such as acids, adjuvants, anticoagulants, antibacterial agents, preservatives, chelating agents, solubilizers, emollients, emulsifiers, flavor humectants, buffers, pH adjusters, stabilizers, suspending agents, sweeteners, thickeners, surfactants, colorants, preservatives, and the like.

[0032] Suitable sweeteners may be selected from sugars such as sucrose, lactose, and glucose, cyclamate and its salts, saccharin and its salts, sucralose, aspartame, and the like.

[0033] Flavoring agents may be selected from natural or synthetic flavors such as strawberry flavor, cherry flavor, orange flavor, green apple flavor, spearmint flavor, peppermint flavor, and the like.

[0034] The solubilizing agent may be selected from sodium lauryl sulfate or complexing agents such as cyclodextrins, ion exchange resins, crown ethers, and the like.

[0035] One of the primary objectives of the present invention was to prepare a product with acceptable stability, and to this end, the compositions of the present invention were subjected to conventional and accelerated stability testing in accordance with current ICH guidelines.

[0036] As a result, the stability of the present invention was good (e.g., total impurities did not increase under normal and accelerated conditions).

[0037] The selection of appropriate materials (such as excipients) should be done carefully to avoid any incompatibility issues or non-compliance with EMA and FDA guidelines on inactive ingredients.

[0038] The following examples illustrate preferred embodiments in accordance with the present invention without limiting the scope or spirit of the invention. [Example]

[0039] Example 1: Compatibility test of flecainide acetate Extensive compatibility studies were performed to identify potential drug-excipient interactions. The compatibility protocol was designed to include two different pH ranges: an acidic pH range with pH values ​​of pH ≤ 4.0, and an alkaline pH range with pH > 7.

[0040] Before evaluating the potential impact of inactive ingredients on the stability of flecainide acetate, the pH stability profile in the specified pH ranges above was determined to guide the design of subsequent compatibility studies. To this end, the compositions shown in Tables 1 and 2 were subjected to stress heating conditions.

[0041] Drug-excipient interactions were monitored for related substances by a stability-indicating HPLC method.

[0042] Example 1 - Compositions 1-3 and 6-8 containing 0.5% flecainide acetate to establish the pH-stability profile of flecainide acetate [Table 1]

[0043] Unless otherwise stated, all steps in this procedure were performed at room temperature.

[0044] Compositions 1 and 3 of Example 1 of the present invention were prepared according to the following steps: Purified water was added to a compounding vessel in an amount of approximately 85% of the total volume, and the entire amount of flecainide acetate was added under stirring. Once complete dissolution was achieved, additional purified water was added to the total volume as needed. The final pH of the solution was measured with a calibrated pH meter, and adjusted to the pH values ​​shown in Table 1 using hydrochloric acid or aqueous sodium hydroxide solution as needed. The results are shown below (see Table 3).

[0045] Composition 2 of Example 1 of the present invention was prepared according to the following steps: Approximately 85% of the total volume of purified water was added to a compounding vessel, and the predetermined amounts of citric acid and sodium citrate were added under stirring. Once complete dissolution was achieved, the entire amount of flecainide acetate was added under stirring, and additional purified water was added to the total volume, if necessary. The final pH value of the solution was measured with a calibrated pH meter, and adjusted to the pH value shown in Table 1 using hydrochloric acid or aqueous sodium hydroxide solution, if necessary. The results for Compositions 1 to 3 of Example 1 are shown below (see Table 3).

[0046] [Table 2]

[0047] Unless otherwise stated, all steps in this procedure were performed at room temperature.

[0048] Compositions 7 and 8 of Example 1 of the present invention were prepared according to the same manufacturing steps as Compositions 1 and 3 of Example 1. Composition 6 of Example 1 of the present invention was prepared according to the following manufacturing steps. Approximately 85% of the total amount of purified water was added to a compounding vessel, and predetermined amounts of sodium dihydrogen phosphate dihydrate and sodium dihydrogen phosphate anhydrous were added with stirring. Once complete dissolution was achieved, the entire amount of flecainide acetate was added with stirring, and additional purified water was added to the total volume as needed. The final pH value of the solution was measured with a calibrated pH meter and adjusted to the pH value shown in Table 2 using hydrochloric acid or aqueous sodium hydroxide solution as needed.

[0049] A lot of precipitation was observed for composition 6 and composition 8, and therefore no analytical work was performed. The results for composition 7 of example 1 are shown below (see Table 3).

[0050] [Table 3] By compatible is meant a clear solution, substantially free of visible particles.

[0051] [Table 4] By compatible is meant a clear solution, substantially free of visible particles.

[0052] [Table 5] By compatible is meant a clear solution, substantially free of visible particles.

[0053] Monitoring revealed that compositions 1 to 3 with pH values ​​below 4.0 remained clear throughout the observation period from T=0 to T=30 days, whereas liquid compositions 6 and 8 of Example 1 with pH values ​​above 7.0 both exhibited precipitates immediately after preparation at T=0. The chemical quality of flecainide acetate as a function of pH was unaffected. The level of degradants produced upon exposure to severe heat stress was negligible across all pH ranges, indicating minimal interaction between pH and moiety reactivity. In contrast, pH, and potentially the type of buffer system, appeared to affect physical stability. The latter was evidenced by the immediate precipitation of both composition 6 of Example 1, to which a phosphate compound was added, and composition 8 of Example 1, to which a saturated solution was formed.

[0054] Although pH fluctuations were not associated with chemical instability, their potential interaction with the dissolution process of flecainide acetate reinforced the need to optimize not only the buffer but also the pH of the solution. Because no pH range was significantly more favorable than another, the acidic range was selected for further monitoring. This choice was supported by the fact that the acidic range is the favorable environment for most preservatives to exert their antimicrobial properties.

[0055] After standardizing the optimal pH range, a series of compatibility studies were conducted to evaluate the stability of flecainide acetate with various excipients. Representatives from the most important excipient categories routinely used in oral liquid formulations were evaluated: cosolvents (i.e., propylene glycol, sorbitol, and glycerol), preservatives (i.e., sodium benzoate and parabens), and sweeteners (i.e., sucralose and sodium saccharin). Binary aqueous solutions of flecainide acetate and candidate excipients were incubated for one month under accelerated ICH conditions and at elevated temperatures. Within the same study, the tendency of selected excipients to inhibit the dissolution kinetics of the active ingredient was monitored by subjecting samples to conditions that could promote supersaturation, i.e., refrigerated conditions (temperatures 2 to 8°C).

[0056] Example 2 - Compositions 9-16 containing 0.5% flecainide acetate were prepared with various excipients to investigate their effect on precipitate formation. [Table 6]

[0057] Compositions 9 to 16 of Example 2 of the present invention were prepared according to the following manufacturing steps. Purified water was added to a compounding vessel in an amount of approximately 85% of the total volume, and the entire amount of various excipients (propylene glycol, glycerol, sorbitol, sucralose, saccharin sodium, sodium benzoate, methylparaben sodium, propylparaben sodium, etc.) was added under stirring until completely dissolved. Flecainide acetate was then added under stirring until completely dissolved, and additional purified water was added to the total volume as needed. The final pH of the solution was measured, and if necessary, adjusted to a pH value of less than about 4.0, specifically a pH value of about 3.5, using hydrochloric acid solution. The production results of the above compositions are shown in the table below.

[0058] [Table 7] NP means not done. BRL means below reporting limit, essentially no visible particles.

[0059] [Table 8]

[0060] Compositions 9, 10, 15 and 16 of Example 2 were not chemically investigated because precipitation was observed upon storage for 30 days.

[0061] [Table 9] ND means not detected.

[0062] [Table 10]

[0063] All compatibility tests demonstrated chemical thermal stability, as evidenced by extremely low levels of degradants. Conversely, physical destabilization occurred with certain excipients in the form of precipitation. The presence of propylene glycol and glycerol inhibited the solubility of flecainide acetate, forcing its salting out. Interestingly, because the thermal solubilization effect already signaled instability, this phenomenon was expected to be even stronger under refrigerated conditions. It is speculated that the reduction in the dielectric constant of water due to the addition of propylene glycol and glycerol minimized the solubilizing capacity of the vehicle, leading to crystallization of the active ingredient. This hypothesis was analytically verified by assay testing on samples containing visible material. Significant potency loss was recorded, which correlated well with the results of visual inspection. Therefore, the inclusion of organic solvents in the liquid vehicle was ruled out.

[0064] Similar effects were observed with methylparaben and propylparaben, and they were excluded from formulation development studies.

[0065] Overall, it became clear that formulating flecainide acetate in solution required a lean aqueous platform containing the minimum necessary ingredients to confer the desired quality and acceptability. The following ingredients were identified as suitable for further evaluation: sucralose, sodium saccharin, sodium benzoate, and sorbitol.

[0066] Example 3: Evaluation / Selection of Buffers Example 3 - Compositions 4a, 4b and 4c containing 0.5% flecainide acetate and various buffers Details of the compositions and their stability results are given in the table below.

[0067] [Table 11]

[0068] Compatibility studies have shown that the type of buffer system is an important variable for the chemical and physical stability of pharmaceuticals. Therefore, compositions with various buffer systems have been evaluated to assess the stability, primarily the physical stability, of the compositions.

[0069] To gain a definitive understanding of the potential interference of buffering components with the dissolution process of the active ingredient itself, conditions capable of stressing dissolution characteristics were employed. Storage was carried out for one month under ambient conditions (temperature 25°C ± 2°C / relative humidity 60% ± 5%) and refrigerated conditions (5°C ± 3°C). Appearance, assay, and impurity measurements were performed before and after storage.

[0070] Compositions 4a, 4b, and 4c of Inventive Example 3 were prepared according to the same manufacturing steps as Composition 2 of Inventive Example 1, and the pH value was adjusted to about 3.0 by adding either a 30% acetic acid solution, a hydrochloric acid solution, or a 30% citric acid solution.

[0071] Bottles of compositions 4a, 4b and 4c of Example 3 were exposed to various storage conditions, and the stability results are shown in Table 12 below. The stability results of compositions 4a and 4c of Example 3 over a period of one month showed that the above compositions of flecainide acetate containing citric acid or acetic acid as an acidifying agent with a final pH value of 3.0 were also stable, providing an acidic pH environment to the dosage form and protecting the active ingredient from degradation (see Table 12).

[0072] [Table 12] ND indicates not detected, and NP indicates not performed.

[0073] Visual observation confirmed that the physical stability of flecainide acetate solutions depends on the type of buffer system. In composition 4b of Example 3, precipitation occurred in the presence of hydrochloric acid, a behavior that intensified upon refrigerated storage. No such solid structures were detected in compositions 4a and 4c of Example 3, which used the organic acids under evaluation. Neither acetic acid nor citric acid interfered with the dissolution process of the active ingredient, even after prolonged exposure to conditions that induce crystal growth. The accumulated results were in good agreement with those described in general monographs. The data generated provided a deeper understanding of the interaction between flecainide acetate and acidifying agents, justifying the selection of acetic acid or citric acid to mediate the aforementioned pH values.

[0074] At this point, it should be clarified that the data on HCl-containing compositions in this study are not inconsistent with those obtained in the compatibility studies. The reason that precipitation was not noted in the pH stability studies of compositions acidified with HCl is that the high energy introduced by heat increases the mobility of solute molecules, making them easier to pass through in solution.

[0075] Finally, citric acid was selected as the most preferred composition of the present invention. Citric acid was chosen for its acceptability benefits, as the very strong acidic odor of acetic acid is unlikely to be effectively masked by formulating agents. The level was fixed at 6.85 mg / ml, which corresponds to the amount required to achieve the desired target pH of 2.8-3.2.

[0076] Example 4 - Composition 5 containing 0.5% flecainide acetate (reference example) [Table 13]

[0077] Unless otherwise stated, all steps in this procedure were performed at room temperature.

[0078] Composition 5 of Example 4 of the present invention, the most preferred composition according to the present invention, was prepared according to the following manufacturing steps: Approximately 85% of the total volume of purified water was added to a compounding vessel, and then a predetermined amount of citric acid was added under stirring at a water temperature of 23-28°C until completely dissolved. To the resulting mixture, the entire amount of sodium benzoate was added under stirring until completely dissolved. Then, flecainide acetate was added under stirring until completely dissolved, and sucralose and cherry flavoring were added sequentially under continuous stirring. A sample of the solution was taken, and the pH value was measured using a calibrated pH meter. The pH value of the final solution was adjusted to a pH value of 2.8-3.2 with the aid of a 30% w / v citric acid solution, if necessary. Additional purified water was then added under stirring to the total volume, if necessary.

[0079] The final solution was then passed through a polypropylene (PP) cartridge filter with a porosity of 30 or 40 μm and filled into bottles designated for oral use.

[0080] To complete the characterization of the compositions of the present invention, the preservative levels were evaluated for antimicrobial protection using the Preservative Efficacy Test (PET), and the sucralose levels and flavor types were evaluated by a sensory panel in terms of taste and aftertaste (palatability test).

[0081] Example 5: Microbiological evaluation of preservatives Example 5 - Compositions 5a, 5b, 5c and 5d containing 0.5% flecainide acetate and various concentrations of sodium benzoate Details of the compositions and their stability results are given in the table below.

[0082] [Table 14]

[0083] Compositions 5a, 5b, 5c, and 5d of Example 5, containing various concentrations of sodium benzoate, were also tested for microbiological stability, where solutions of Compositions 5a, 5b, 5c, and 5d were stored in amber glass bottles at room temperature. Stability was evaluated at days 0, 14, and 28 under both "open" and "pre-open" conditions for a preservative-containing control composition. The bottles were opened under non-sterile conditions. Each analysis was performed in duplicate.

[0084] Microbiological analysis was performed using the Preservative Efficacy Test (PET) according to the European Pharmacopeia monograph for non-sterile products. The European Pharmacopeia requirement is a total aerobic microbial count (TAMC) of 10 2 CFU / mL or less, total yeast and mold count (TYMC) 10 1 This indicates less than CFU / mL and the absence of Escherichia coli.

[0085] All compositions tested, 5a, 5b, 5c and 5d, gave satisfactory preservative efficacy test results. The kill rates exhibited by different levels of sodium benzoate are detailed in the table below.

[0086] [Table 15]

[0087] [Table 16]

[0088] [Table 17]

[0089] [Table 18]

[0090] The results demonstrated that all PET tests met the Ph.Eur.Standards for antimicrobial efficacy as specified in §5.1.3 "Efficacy of antimicrobial preservation." Specifically, the number of bacteria and yeast / fungi recovered per gram was readily reduced by greater than 3 and 1 log reductions, respectively, with no increase observed at 28 days.

[0091] The concentrations of sodium benzoate employed, ranging from 0.6 to 1.2 mg / ml, showed sufficient bactericidal activity against either Gram-positive or Gram-negative bacteria, while a concentration-dependent antifungal activity was observed. The latter was reflected in the microbial quality of composition 5d, which contained the lowest level of preservative (0.6 mg / ml), where relatively high microbial counts of Aspergillus brasiliensis (expressed as low log reductions) were recorded. The reductions, which were sufficient to meet preservative standards, indicated a higher sensitivity of the developed carrier against this pathogen.

[0092] Example 6: Preference testing and evaluation of sucralose and flavoring agents [Table 19]

[0093] JPEG2025540537000020.jpg88159

[0094] According to the participants' verbal evaluation, the main taste quality requiring improvement was sourness. The highest score was given to composition 5f, which contained 1.2 mg / ml sucralose and 0.5 mg / ml cherry flavor. According to the participants' responses, compositions 5e and 5f were satisfactorily palatable, with the latter taking the lead due to its additive effect on taste and odor. For compositions 5g and 5h, deterioration of the sensory characteristics was reported when cherry flavor was replaced with orange and strawberry flavors. These flavors accentuated the sourness of the formulation, justifying their exclusion from the final formulation.

[0095] While the present invention has been described with respect to particular embodiments, it will be apparent to those skilled in the art that various changes and modifications may be made in the present invention without departing from its spirit and scope, as defined in the appended claims.

Claims

1. A storage-stable liquid pharmaceutical composition for oral administration comprising flecainide or a pharmaceutically acceptable salt thereof as an active ingredient, wherein the active ingredient is present in the range of 1 to 30 mg / mL, and the composition has a pH value of less than 4.

0.

2. 2. The liquid composition of claim 1, wherein the active ingredient is present in the range of 4 to 10 mg / mL, preferably about 5 mg / mL.

3. 2. The liquid composition of claim 1, wherein the pH value is in the range of 2.8 to 3.2, preferably about 3.

0.

4. 2. The liquid composition of claim 1, wherein the flecainide is in the form of an acetate salt.

5. 10. The liquid composition of claim 1, wherein the composition further comprises at least one pharmaceutically acceptable excipient selected from a sweetener, a buffering agent, a preservative, a pH adjusting agent, a solubilizing agent, a flavoring agent, or a mixture thereof.

6. 10. The liquid composition of claim 1, wherein the composition comprises a buffer system comprising acetic acid, citric acid, or a mixture thereof.

7. 10. The liquid composition of claim 1, wherein the composition comprises sucralose as a sweetener.

8. 10. The liquid composition of claim 1, wherein the composition comprises cherry flavor as a flavoring agent, preferably the cherry flavor is present in the range of about 0.5 mg / mL.

9. 2. The liquid composition of claim 1, wherein the composition comprises sodium benzoate as a preservative, preferably the sodium benzoate is present in the range of 0.6 to 1.2 mg / mL.

10. A storage-stable liquid composition comprising approximately 5 mg / mL flecainide acetate, sucralose, sodium benzoate, and a buffer system comprising citric acid, acetic acid or a mixture thereof, wherein the liquid composition has a pH value in the range of 2.8 to 3.

2.

11. The liquid composition of claim 10, wherein the composition has a pH value of about 3.

0.

12. A liquid composition as described in claim 10, wherein the composition contains cherry flavoring as a flavoring agent, preferably the cherry flavoring is present in the range of about 0.5 mg / mL.

13. The liquid composition of claim 10, wherein the sodium benzoate is present in the range of 0.6 to 1.2 mg / mL.

14. A process for the preparation of a liquid composition according to any one of claims 1 to 13, comprising: (a) dissolving at least one excipient selected from a buffer system and / or a preservative in purified water; (b) adding the entire amount of flecainide or a salt thereof to the obtained solution of step (a) and stirring until completely dissolved; (c) optionally adding at least one excipient selected from sweeteners and / or flavoring agents to the solution of step (b); (d) adjusting the pH of the final solution to less than 4.0 using citric acid solution, or hydrochloric acid or sodium hydroxide solution; The process comprising:

15. 15. The process of claim 14, further comprising filtering the solution of step (d) through a cartridge filter, preferably having a nominal porosity of 30 μm or 40 μm.

16. 15. The process of claim 14, wherein in step (a) sodium benzoate is added as a preservative.

17. 15. The process of claim 14, wherein in step (c) sucralose is added as a sweetener and / or cherry flavoring is added as a flavoring.